Translational research in the genomic era: OPPERA study
- Luda Diatchenko1
© Diatchenko; licensee BioMed Central Ltd. 2014
Published: 15 December 2014
Temporomandibular Disorder (TMD) tends to coexist with other chronic pain conditions in affected individuals and is characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of this condition is largely unknown, the scientific field lacks biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors .
Materials and methods
The large human study named OPPERA, Orofacial Pain Prospective Evaluation and Risk Assessment Study, measures both phenotypic and genotypic markers in the TMD patients. The phenotypic markers of greatest interest include measures of pain amplification and psychological measures such as emotional distress, somatic awareness, psychosocial stress and catastrophizing. Genetic markers are also measured in a study by genotyping 2,924 single-nucleotide polymorphisms representing 358 genes known to be involved in systems relevant to pain perception .
The OPPERA findings provided evidence for few single single-nucleotide polymorphisms to be associated with risk of TMD . Furthermore, several single-nucleotide polymorphisms exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds for association with intermediate phenotypes shown to be predictive of TMD onset  One of the genes on which we focused our initial research efforts on was the epidermal growth factor receptor (EGFR). EGFR is activated by numerous endogenous ligands that traditionally promote cellular growth, proliferation and tissue regeneration. We first identified that SNPs in the gene loci encoding for EGFR and EREG are associated with the risk of chronic TMD in OPPERA and two other independent human cohorts. Subsequent experiments in animal models reveal the functional involvement of these proteins in the pain pathway, show pharmacological and genetic modulation of pain behavior in rodents and Drosophila, and define the relevant signaling pathway. EGFR–ErbB-4 heterodimer activation by EREG produces pain by regulating the PI3K/AKT/mTOR translational machinery and matrix metalloproteinase-9. As a result of these studies, EREG and EGFR–ErbB-4 can be viewed as novel targets for analgesic development.
Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine.
No financial relationships to disclose.
This abstract is being presented on behalf of an OPPERA study group.
- Maixner W, Diatchenko L, Dubner R, Fillingim RB, Greenspan JD, Knott C, Ohrbach R, Weir B, Slade GD: Orofacial pain prospective evaluation and risk assessment study--the OPPERA study. J Pain 2011,12(11 Suppl):T4–11.e1–2.PubMed CentralPubMedView ArticleGoogle Scholar
- Smith SB, Maixner DW, Greenspan JD, Dubner R, Fillingim RB, Ohrbach R, Knott C, Slade GD, Bair E, Gibson DG, Zaykin DV, Weir BS, Maixner W, Diatchenko L: Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. J Pain 2011,12(11 Suppl):T92–101.PubMed CentralPubMedView ArticleGoogle Scholar
- Smith SB, Mir E, Bair E, Slade GD, Dubner R, Fillingim RB, Greenspan JD, Ohrbach R, Knott C, Weir B, Maixner W, Diatchenko L: Genetic variants associated with development of TMD and its intermediate phenotypes: the genetic architecture of TMD in the OPPERA prospective cohort study. J Pain 2013,14(12 Suppl):T91–101.PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.